18-oxygenated-delta-etiocholene-17beta-carboxylic acid derivatives



' 18-0XYGENA'IED-A -ETICHOLENE flp-CAR-- BOXYLICACID DERIVATIVES2,847,425 Patented Au 12, 1958 wherein R and R are carbonyl or hydroxylgroups and can be the same or difierent groups. These compounds areuseful in the preparation of ll-dehydrocorticosterone, Kendalls compoundA, an adrenocortical hormone of use 5 in clinical treatment of disordersresulting from loss of ka g E 3252 gsg gi i g $355: adrenal function. Asan example of this, the 18,20-1ac- Princeton, N. J., assignors to Merck& 00., Inc., Rahtone of y yq I N, J, r i f N v J s boxylic acid can bereacted with hydrazine to open the c lactone ring thereby forming thecorresponding hydrazide ggg gg f ggm gg g ggg 22335 i 3:: 10 which ontreatment with an excess of methane sulfonyl vemberad, 1955 srial No.550,179 chloride and then desulfurization with deactivated Raney l vnickel is converted to A -3,1l-dioxo-ctiocholene-17,B-car- 1 8 Clmms- I260-3971) boxylic acid. The further conversion of the latter comhiapplication i a i i f our copending 1 pound to Kendallscompound Aacetate can be efiected cation s i 452,093, fil d October 1 954 by theclassical diazoketone synthesis involving treat- This invention relatesto derivatives of A -etiocholenic ment of the dike) acid W oxalylchloride followed acid and particularly to 18-0Xygenated-A-eti0choleneby reaction of the acid chloride with diazomethane and 17fi-carb oxylic acid derivatives and to processes for preacetic acid.These reactions may be chemically repreparing these compounds. 20 sentedas follows:

CHzOH CH:QSOQCH| 4 n I 0v l The lS oXygenatedetiocholene-l7fi-carboxylic acid def rivatives which are the subject ofthe invention have the following general formula:

ii I rwmgig The compounds of the invention are prepared by re-- actingthe 18,20-1actone of A -3-Oxo-18-hydroxy-11fi,18-'epoxyetiocholene-17,8-carboxylic acid (compound I) with a a base to formA -3,18-dioxo-1lfl-hydroxyetiocholene-17,6-

CHO o-c1\1 0: (30:11:

g i i 0:

ersea- QQmQQmQ-ln on on. 1 29.. com.

Compound V Compound v1 The 18,20-lactone ofA%:3:oxo-18-hydroxy-11fi,18:epoxyeticcholene-l7 3-carbpxylic acid isreacted with a base to form ,18-dioxo-1lfi-hydroxetioeholene-17,8-cafbox-" ylic acid. Any of the conventionalbases can be used, such as aqueous solutions of alkali or alkaline earthmetal hydroxides, carbonates, bicarbonates, or alkoxides, although it ispreferred to use alcoholic solutions of alkali metal hydroxides. Typicalexamples of suitable bases are sodium hydroxide, potassium hydroxide,sodium carbonate, potassiurn bicarbonate, sodium methoxide, andpotassium 'ethoxide The reaction is carried'oilt atapproximately 0 to100 C. with 85 to 100 C. being preferred. The reaction is usuallycompleted in a fewminutes toa half houfalthough," with certain of thereactants the. The reaction; may be carried out iri any of the usualorganicsolvents,

reaction time is extended to a. few days.

such as alcohols, although it is necessary to have a sni'all amount ofwater present. The product is recovered from the reaction mixture 'byacidifying the extracting with an immiscible organic solventfsuchas'ethyl acetate:

The A -3 ,18-dioxo1 1/3'- hyc lr oxyetiocholene 1 7fl-carboxylic"acid'is reduced by reaction'with n allgalimetal borohydride 'to" form15 -13 ,llfl,18 trihydroxyetiocholene-175 carb'oxylic acid.The"reactioncan"be carried out in a solvent, such as water,methanolfethanoljor tetrahydrofuran. It is 'desirable'to add a"s'm'a'll"amount of a base to aid in solubilizing'the' steroid. The temperature"of the reaction'ma'y vary from abjout- 4Q.to' '01"C.," but is;preferably from 90 'to 'IOO C'." The reactionusually requires from oneto threehoursfor completionalth'ough;

longer or shorter periods may be; usedlfThe" a1 'ali'metal borohydride,which is prefi ably use'd in excess of the 4 nuim laramcunt,is..a..b.0ron. compoundhavinganalkali metal associated with a groupconsisting of a boron atom and at least one and up to four reactivehydrogen atoms. When there are less than four hydrogen atoms, the groupcontaining the boron atom may contain one to three atoms other thanhydrogen or one to three radicals, which atoms or radicals arerelatively inert and non-reactive with respect to the reducing actioncharacteristic of the hydrogen atoms of these compounds, or acombination of such atoms other than hydrogen and radicals so long as atleast one hydrogen atom is present and so long as the total number ofatoms including hydrogen and radicals is four. Typical examples of-these compounds are sodium borohydride, lithium borohydride, sodiumtriethylborohydride and potassium borohyjdride. The product can berecovered from thevreaction. mixture by acidifying and extracting with;an immiscible-"solvent; such "as ether, chloroform, ethylene chlorideorethyl acetate.

The A -3, l 1/3,18-trihydroxyetiocholene 17Bcarboxylic acid, is heatedto form thecorresponding 18,20-lactone. The heating is preferablycarried btitat approximately 200 C. althoughhigher or lower temperaturescan'be used, such asfrom to. 300 C. The heatingcan be. carried out in ahigh boiling unreactive solvent, suchlas diphenylether. The reaction ispreferably'icarriedout in vacuo or in a nitrogen atmosphere. The,reaction proceeds rapidly usually requiring only one to fifteen minutesfor completion. The, productlcontaining, only? .unreacted acid 1'5 Q X WY P Iifi d by partitioning. between ethyl acetate andaqueoussodiumbicarbonate.

5. 8,Zthlatgtgne.ofrtf-Z; 111,3,18-trihydroxyetiocholene-- jfl -pa yli conv rted; to, the. co r p 3-oxo-ll-hydroxy lactone by oxid ternperature(25-30 C.). Other oxidizing agents can, however, be used which willselectively oxidize the three position Without affecting the elevenposition. Typical examples ofisu'chi agents which may be used are N-bromoamides and hl-brdmoimides, such as N-bromoacetamide andN-brom'osuccinimide. The oxidation may be carried out in a solvent, suchas acetone, chloroform, or the like and preferably at a.'te mperature ofabout 20 to 40 C. The product is conveni e'ntly recovered byextractionw'ith an immiscible solvent.

-'The 18,20-lactone of A -3, 11,3,18-trihydroxyetiocholenel7ficarboxylic acid and the 3-6xo-11-hydroxy-lactone can be oxidized to thecorresponding 18,20-1actone of A -3,ll-dioxo-1S-hydroxyetiocholene-17S-carboxylic acid. The oxidizing agent can be compounds of hexavalentchromium, such as chromic acid or chromyl chloride, chromiuni trioxideand also permanganates. The reaction is preferably carried out in aninert solvent, such as pyridine, acetic acid or benzene. The preferredoxidizing agents are chromium trioxideifi pyridine and chromium nioxidein acetic acid. The reaction proceeds favorably at O to 40 C. withroomternperature (ZS-30 C.) being the most convenient. T hereacti'onrequires from one to twenty hours for completion. The product isconveniently recovered by adding water to the reaction mixture andextracting with ethyl acetate. i

l wi m l sar s ea sapateerstaf 1 1 fi l, W

EXAMPLE-l A -3,18-dioxo-1Ifi-hydroxyetiocholened7B-carboxylic acidSodium hydroxy solution (2.5 ml. of 2.5 N) is added to 5.2 mg. of the18,20-1actone of A -3-oxo-18-hydroxy- 11 6,18-epoxyetiocholene l78-carboxylic acid in 2.5 ml. of warm methanol. The solution is boiled onthe steam cone for five minutes with loss of-most of the methanol andappearance of a yellow color. trace of crystalllne solid is obtained byethyl acetate extraction of the cooled alkaline solution. Ethyl acetateextraction after acidification followed .decolorization with Norit inacetone ion. The reaction is; conveniently effected with manganesedioxide at room observed at ca. 220 C.; melting with discolorationoccurs at 285 to 300 C.

EXAMPLE 2 A -3,11}8,1S-trihydroxyetiocholene-I7fi-carb0xylic acid Sodiumborohydride (15 mg.) is added to 6.4 mg. of A-3,1118,18-trihydroxyetiocholene-l7fi-carboxylic acid in 1 ml. of 0.05 Nsodium hydroxide solution, and the reaction mixture heated on the steamcone (100 C.) for 1.5 hours. Ethyl acetate extraction afteracidification to pH 2 gives 6.0 mg. of amorphous white solid trihydroxyacid (2),

N121? 2.9-3.1 and 5.73-5.85p EXAMPLE 3 18,20-lactone of 13-3.]113,18-trihydrxyetiocholene-1 7,8- carbaxylz'c acid x fig ae and5.72,.

EXAMPLE 4 18,20-lact0ne of A -3-0x0-11,18-dihydraxyetioch0lene-17/8-carboxylic acid The 18,20-lactone of A-3,115,18-trihydroxyetiocholene- 17B-carboxylic acid (4 mg.) isdissolved in acetone and manganese dioxide (10 mg.) is added. Themixture is stirred at room temperature for one and a half hours. Themanganese dioxide is filtered oif and the solvent removed by subjectingthe mixture to distillation in vacuo.

EXAMPLE 18,20-lact0ne of 11 -3.] I-diox0-18-hydr0xyetiocholene-17,3-carboxylic acid The 18,20-lactone of A-3,1113,18-trihydroxyetiocholene 1713-carboxylic acid (4 mg.) insolution in 0.1 ml. of pyridine is added to the complex form 11 mg. ofchromiurn trioxide and 0.2 ml. of pyridine and the mixture keptovernight at 28 C. The reaction mixture, which contains much dark solid,is then brought to pH 4 with hydrochloric acid and extracted with ethylacetate. An ethyl acetate solution of the amber residue is passedthrough a short column of Norit to yield 3.0 mg. of granular crystallinediketo-lactone (4). This compound softens at 211 C. and melts at 230-237C.,

Max.

Any departure from the above description which conforms to the presentinvention is intended to be included within the scope of the claims.

What is claimed is:

l. A -3,l8-dioxo-1I/B-hydroxyetiocholene 17,8 carbox ylic acid.

2. A -3,1 113,18 trihydroxyetiocholene 17 pi carboxylic acid.

3. A process which comprises reacting the 18,20-lactone of A-3-oxo-18-hydroxy-1 1B,18-epoxyetiocholene-17B-carboxylic acid with abase to form A -3,18-dioxo-l1fl-h droxyetiocholene-l7fi-carboxylic acid.

4. A process which comprises reacting A -3,18-dioxo-1lfi-hydroxyetiocholene-17B-carboxylic acid with an alkali metalborohydride to form A -3,115,18-trihydroxyetiocholene-17fi-carboxylicacid.

5. A process which comprises reacting the 18,20- lactone of A-3-oxo-18-hydroxy-1 1B,18-epoxyetiocholene- 17/3-carboxylic acid with analcoholic solution of an alkali metal hydroxide to produce A-3,18-dioxo-11fi-hydroxyetiocholene-17fl-carboxylic acid.

6. The process of claim 5, wherein the reaction is carried out at atemperature of 0 to C.

7. A process which comprises reacting A -3,18-dioxol1,B-hydroxyetincholene-17,8-carboxylic acid with an alkali metalborohydride at a temperature of about 40 to 100 C. to produce A-3,11/3,18-trihydroxyetiocho1ene-17B-carboxylic acid.

8. A compound selected from the class consisting of A -3,18-dioxo 11 Bhydroxyetiocholene 17/3 carboxylic acid, and A-3,11B,1S-trihydroxyetiocholene-17B-carboxylic acid.

Simpson: Helv. Chim. Acta, vol. 37 (1954), pp. 1200-1223.

8. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF$4-3,18-DIOXO-11B-HYDROXYETIOCHLOENE- 17B-CARBOXYLIC ACID, AND$4-3,11B,18-TRIHYDROXYETIOCHOLENE-17B-CARBOXYLIC ACID.